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Vol. 59, Issue 5, 1108-1118, May 2001
Subunit on Allosteric Modulation of Ion Channel
Function in Stably Expressed Human Recombinant
-Aminobutyric AcidA Receptors Determined Using
36Cl Ion Flux
Merck Sharp and Dohme Research Laboratories, Neuroscience Research
Centre, Harlow, Essex, United Kingdom
Inhibitory 
-aminobutyric acid (GABA)A receptors are
subject to modulation at a variety of allosteric sites, with
pharmacology dependent on receptor subunit combination. The influence
of different 
subunits in combination with 
32s was examined in
stably expressed human recombinant GABAA receptors by
measuring 36Cl influx through the ion channel pore.
Muscimol and GABA exhibited similar maximal efficacy at each receptor
subtype, although muscimol was more potent, with responses blocked by
picrotoxin and bicuculline. Receptors containing the 3 subunit
exhibited slightly lower potency. The comparative pharmacology of a
range of benzodiazepine site ligands was examined, revealing a range of
intrinsic efficacies at different receptor subtypes. Of the
diazepam-sensitive GABAA receptors (1, 2, 3,
5), 5 showed the most divergence, being discriminated by zolpidem
in terms of very low affinity, and CL218,872 and CGS9895 with different
efficacies. Benzodiazepine potentiation at 332s with
nonselective agonist chlordiazepoxide was greater than at 1, 2,
or 5 (P < 0.001). The presence of an 4
subunit conferred a unique pharmacological profile. The partial agonist bretazenil was the most efficacious benzodiazepine, despite lower 4
affinity, and FG8205 displayed similar efficacy. Most striking were the
lack of affinity/efficacy for classical benzodiazepines and the
relatively high efficacy of Ro15-1788 (53 ± 12%), CGS8216 (56 ± 6%), CGS9895 (65 ± 6%), and the weak partial
inverse agonist Ro15-4513 (87 ± 5%). Each receptor subtype was
modulated by pentobarbital, loreclezole, and
5-pregnan-3-ol-20-one, but the type of subunit influenced the
level of potentiation. The maximal pentobarbital response was
significantly greater at 432s (226 ± 10% increase in
the EC20 response to GABA) than any other modulator. The
rank order of potentiation for pregnanolone was 5 > 2 > 3 = 4 > 1, for loreclezole 1 = 2 = 3 > 5 > 4, and for pentobarbital 4 = 5 = 2 > 1 = 3.
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